Outcome of fetuses with gastroschisis after modification of prenatal management strategies : Prenatal management and outcome of gastroschisis.

PURPOSE: To improve the outcome of fetuses with gastrochisis several studies evaluated prenatal predictors. But there are different guidelines established and therefore the prenatal care is not standardized. With our study we wanted to evaluate the outcome of fetuses with gastroschisis after modification of prenatal management strategies at the Department of Obstetrics and Gynecology of the University Hospital Münster. METHODS: In this explorative retrospective study of 39 fetuses with gastroschisis, we compare the clinical outcome between two management groups. In the first group (group 1, n = 14) prenatal indication for delivery was confirmed by a subjective evaluation of the small bowel diameter and the wall thickness without established cut-off values for these parameters. In the second group (group 2, n = 25) certain limits for the small bowel diameter (25 mm) and the wall thickness (2.5 mm) were used for fetal surveillance. RESULTS: Noticeable differences between the two groups regarding birth weight, weight centile, arterial pH, small bowel diameter, wall thickness, adverse bowel condition and re-operations could not be observed. In group 2, delivery was earlier (p = 0.011), and a lower rate of prenatal complications was observed (p = 0.016). CONCLUSION: To avoid adverse prenatal complications we recommend the observation of fetuses with gastroschisis by sonographic monitoring of the small bowel diameter and the wall thickness.

GABA-from Inhibition to Cognition: Emerging Concepts.

Neural functioning and plasticity can be studied on different levels of organization and complexity ranging from the molecular and synaptic level to neural circuitry of whole brain networks. Across neuroscience different methods are being applied to better understand the role of various neurotransmitter systems in the evolution of perception and cognition. GABA is the main inhibitory neurotransmitter in the adult mammalian brain and, depending on the brain region, up to 25% of the total number of cortical neurons are GABAergic interneurons. At the one end of the spectrum, GABAergic neurons have been accurately described with regard to cell morphological, molecular, and electrophysiological properties; at the other end researchers try to link GABA concentrations in specific brain regions to human behavior using magnetic resonance spectroscopy. One of the main challenges of modern neuroscience currently is to integrate knowledge from highly specialized subfields at distinct biological scales into a coherent picture that bridges the gap between molecules and behavior. In the current review, recent findings from different fields of GABA research are summarized delineating a potential strategy to develop a more holistic picture of the function and role of GABA.

Pressure-dependent diffusion coefficients and haven ratios in cation-conducting glasses.

The influence of hydrostatic pressure on diffusion and ionic conduction is providing deeper insights into the atomistic mechanisms of ionic motion in glasses. We have studied the tracer diffusion of 22Na in a sodium borate glass and of 86Rb in a rubidium borate glass as functions of hydrostatic pressures. The activation volumes of tracer diffusion are DeltaVD(Rb) = 33.5 cm3 mol-1 and DeltaVD(Na) = 6.1 cm3 mol-1. In comparison, the activation volumes of charge diffusion obtained recently from the pressure dependence of conductivity are smaller: DeltaVsigma(Rb) = 7.2 cm3 mol(-1) and DeltaVsigma(Na) = 2.8 cm3 mol(-1). These differences, where (DeltaVD - DeltaVsigma) > 0, imply that the Haven ratios decrease with pressure. This effect is particularly significant for the rubidium borate glass. Starting from basic equations of linear response theory for mass and charge transport, we develop a model that accounts for these experimental findings. The difference between the activation volumes, DeltaVD and DeltaVsigma, and the pressure-dependent Haven ratios are consequences of collective movements of ions in glass, implying a concerted motion of ions in a chain- or caterpillar-like fashion. In our treatment, it is a vacant site (with ions jumping into it successively) that moves along an extended pathway. Hence, we regard vacant sites as the carriers of charge and ions as the carriers of diffusing matter. The decrease of the Haven ratio with pressure is attributed to the influence of pressure on the topology of the conduction pathways, which are progressively straightened out with increasing pressure.

Neurobiological after-effects of non-invasive brain stimulation.

BACKGROUND: In recent years, many studies have evaluated the effects of noninvasive brain stimulation (NIBS) techniques for the treatment of several neurological and psychiatric disorders. Positive results led to approval of NIBS for some of these conditions by the Food and Drug Administration in the USA. The therapeutic effects of NIBS have been related to bi-directional changes in cortical excitability with the direction of change depending on the choice of stimulation protocol. Although after-effects are mostly short lived, complex neurobiological mechanisms related to changes in synaptic excitability bear the potential to further induce therapy-relevant lasting changes. OBJECTIVE: To review recent neurobiological findings obtained from in vitro and in vivo studies that highlight molecular and cellular mechanisms of short- and long-term changes of synaptic plasticity after NIBS. FINDINGS: Long-term potentiation (LTP) and depression (LTD) phenomena by itself are insufficient in explaining the early and long term changes taking place after short episodes of NIBS. Preliminary experimental studies indicate a complex scenario potentially relevant to the therapeutic effects of NIBS, including gene activation/regulation, de novo protein expression, morphological changes, changes in intrinsic firing properties and modified network properties resulting from changed inhibition, homeostatic processes and glial function. CONCLUSIONS: This review brings into focus the neurobiological mechanisms underlying long-term after-effects of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) recently obtained from in vitro and in vivo studies, both in animals and humans.

On the significance of temporally structured activity in the dorsal lateral geniculate nucleus (LGN).

Higher organisms perceive information about external or internal physical or chemical stimuli with specialized sensors that encode characteristics of that stimulus by a train of action potentials. Usually, the location and modality of the stimulus is represented by the location and specificity of the receptor and the intensity of the stimulus and its temporal modulation is thought to be encoded by the instantaneous firing rate. Recent studies have shown that, primarily in cortical structures, special features of a stimulus also are represented in the temporal pattern of spike activity. Typical attributes of this time structure are oscillatory patterns of activity and synchronous discharges in spatially distributed neurons that respond to inputs evoked by a coherent object. The origin and functional significance of this kind of activity is less clear. Cortical, subcortical and even very peripheral sources seem to be involved. Most of the relevant studies were devoted to the mammalian visual system and cortical findings on temporally structured activity were reviewed recently (Eckhorn, 1994, Progr. Brain Res., Vol. 102, pp. 405-426; Singer and Gray, 1995, Annu. Rev. Neurosci., Vol. 18, pp. 555-586). Therefore, this article is designed to give an overview, especially of those studies concerned with the temporal structure of visual activity in subcortical centers of the primary visual pathway, which are the retina and the dorsal lateral geniculate nucleus (LGN). We discuss the mechanisms that possibly contribute to the generation and modulation of the subcortical activity time structure and we try to relate to each other the subcortical and cortical patterns of sensory activity.

Ten Years of Theta Burst Stimulation in Humans: Established Knowledge, Unknowns and Prospects.

BACKGROUND/OBJECTIVES: Over the last ten years, an increasing number of authors have used the theta burst stimulation (TBS) protocol to investigate long-term potentiation (LTP) and long-term depression (LTD)-like plasticity non-invasively in the primary motor cortex (M1) in healthy humans and in patients with various types of movement disorders. We here provide a comprehensive review of the LTP/LTD-like plasticity induced by TBS in the human M1. METHODS: A workgroup of researchers expert in this research field review and discuss critically ten years of experimental evidence from TBS studies in humans and in animal models. The review also includes the discussion of studies assessing responses to TBS in patients with movement disorders. MAIN FINDINGS/DISCUSSION: We discuss experimental studies applying TBS over the M1 or in other cortical regions functionally connected to M1 in healthy subjects and in patients with various types of movement disorders. We also review experimental evidence coming from TBS studies in animals. Finally, we clarify the status of TBS as a possible new non-invasive therapy aimed at improving symptoms in various neurological disorders.

The dynamic spatio-temporal behavior of visual responses in thalamus and cortex.

Due to eye and object movements the visual world changes on a rather fast time scale and the neuronal network of the primary visual pathway has to immediately react to these changes. Accordingly the neuronal activity patterns in the visual thalamus and cortex show a pronounced dynamic behavior which reenters the circuitry such that the actual cell responses are also guided by the activation history of the network. Thus, spatial and temporal aspects of visual receptive fields change not only by means of the actual visual stimulation hut also as a consequence of the state of the network. In this short review we summarize the different aspects which can influence the temporal firing patterns of cells in the visual thalamus (lateral geniculate nucleus, LGN) mainly by demonstrating how their inter-spike interval distributions will change. We then show that these firing patterns are able to change the spatial shape of receptive fields in the visual cortex (see Fig. 12 for a summary diagram). Finally, by means of a biophysical model, we will argue that the observed changes could serve to adjust the temporal and spatial resolution within the primary visual pathway to the different demands for information processing in an attentive as compared to a non-attentive state.

Quantitative aspects of the state-dependent co-variation of cat lateral geniculate and perigeniculate visual activity.

The quantitative relationship between EEG-related changes in the visual activity of perigeniculate (PGN) and lateral geniculate (LGN) neurons with overlapping receptive fields was analyzed in the anesthetized and paralyzed cat. While transient response peaks were independent of the EEG state, we found opposite changes in spontaneous activity and tonic visual responses, with PGN cells increasing and LGN cells decreasing their spontaneous/tonic activity with increasing EEG delta activity in most cases. The tonic firing rates of PGN and LGN cell pairs were clearly correlated with a slope of about -0.5. Thus, LGN firing was low when PGN activity was high and vice versa. With a change from low to high EEG delta activity the difference between the tonic responses of PGN and LGN cells increased on average by 50 spikes/s, both for the whole population and at the single cell level, indicating that state-dependent changes in retino-geniculate transmission are regulated by a distinct ratio of PGN-LGN activity.

Possible enhancement of GABAergic inputs to cat dorsal lateral geniculate relay cells by serotonin.

The possible enhancement of inhibitory inputs to relay cells of the dorsal lateral geniculate nucleus (dLGN) by serotonin (5-HT) was studied during blockade of GABAA-receptor mediated inhibition with bicuculline (BICU). Visually induced spike activity of single units was recorded during simultaneous micro-iontophoretic application of BICU or 5-HT. All 28 relay cells studied were disinhibited by BICU and strongly inhibited by 5-HT. The responses during BICU or 5-HT were on average statistically different from the controls (p < 0.01, Student's t-test). The inhibition by 5-HT could be almost totally abolished by the simultaneous application of BICU and responses during the combined application of both substances were only slightly different from those obtained during BICU alone (p < 0.3).

Changes in response modulation of cat perigeniculate neurons related to EEG state and application of neuromodulators.

Spike activity of single perigeniculate (PGN) neurons was recorded in the anaesthetized (N2O/halothane) and paralysed cat during presentation of moving gratings of optimal spatial frequency. Typically, the ongoing (tonic, spontaneous) activity of PGN cells increased during a rise in EEG delta power accompanied by a reduction and often a total loss of spike rate modulation by the moving grating. The opposite behaviour was found when the EEG delta power vanished. Micro-iontophoretically applied acetylcholine (ACh) had an effect similar to a decrease in EEG delta power, decreasing ongoing activity but increasing the response modulation depth. The opposite effect could be achieved with the excitatory action of serotonin (5-HT), mimicking a strengthened EEG delta power. These data support previous data indicating that PGN neurons contribute to spatio-temporal tuning of subcortical visual activity in a state-dependent way.

Utilizing latency for object recognition in real and artificial neural networks.

A consistent analysis of a visual scene requires the recognition of different objects. In vertebrate brains this could be achieved by synchronization of the activity of disjunct nerve cell assemblies. During such a process cross-talk between spatially adjacent image parts occurs, preventing efficient synchronization. Temporal differences, naturally introduced by stimulus latencies in every sensory system, were utilized in this study to counteract this effect and strongly improve network performance. To this end in our model the image is 'spread out' in time as a function of contrast-dependent visual latencies, and synchronization of cell assemblies occurs without mutual disturbance. The network model requires a direct link between visual latencies and the onset of synchronous oscillations in cortical cells. This was confirmed experimentally.

Changes of contrast gain in cat dorsal lateral geniculate nucleus by dopamine receptor agonists.

The modulatory effects of dopamine (DA) on the contrast gain of retino-geniculate transmission were tested with local micro-iontophoretical application of DA and the DA receptor agonists SKF38393 (SKF, D1/D5) and quinpirole (QUIN, D2/D3/D4) while recording visually induced spike activity of relay cells of the dorsal aspect of cat lateral geniculate nucleus (dLGN) in the anesthetised and paralyzed preparation. DA and QUIN could either facilitate or inhibit visual activity in a dose-dependent fashion: small amounts caused a facilitation while larger quantities resulted in a more (DA) or less (QUIN) strong inhibition. The effect of SKF was almost always suppressive and increased with the amount of drug applied. The absolute change in activity was depending on stimulus contrast and the strength of the elicited response: facilitation and inhibition of activity was proportional to stimulus contrast and response strength and thus resulted in a changed contrast gain. The results indicate that the visual deficits found in Parkinson's disease patients my be not solely related to retinal dysfunctions.

Corticofugal feedback improves the timing of retino-geniculate signal transmission.

The temporal accuracy of visually induced spike patterns can be expected to deteriorate with increasing distance from the retina due to synaptic noise and other sources of activity unrelated to the retinal signal. Here we report the opposite effect: the interspike interval distributions of relay cells of cat lateral geniculate nucleus (LGN) are sharper than those of their retinal afferents. A biophysically realistical simulation of the retino-cortical pathway, including excitatory cortico-geniculate feedback, produced a similar effect. Without the feedback the mean firing rate in the LGN dropped and interval peaks broadened by an average of 25%. The same effect was found during reversible experimental inactivation of the visual cortex in cat. This indicates that cortico-geniculate feedback could be employed to improve the temporal accuracy of signal transmission.

High-frequency (300-800 Hz) components in cat geniculate (dLGN) early visual responses.

We analysed the early visual responses of relay cells of the dorsal part of cat lateral geniculate nucleus (dLGN) for the occurrence and characteristics of high-frequency (>300 Hz) spike patterns comparable to the high-frequency oscillations (HFO) found in the human somatosensory system. By using a special algorithm for correcting response latency, we can show that the vast majority of dLGN visual responses which were elicited by a sudden change in contrast show HFOs in the range of 300 to more than 800 Hz. After response time correction these HFOs are clearly visible in summed responses, indicating that these patterns are highly reproducible by identical stimuli. On this basis we analysed the HFOs in more detail. We found the oscillation frequency to increase with stimulus contrast and the area of the receptive field centre covered by an excitatory stimulus. Inhibition reduces the oscillation frequency as demonstrated with additional stimulation of the antagonistic surround of the receptive field and by blocking inhibition with micro-iontophoretical application of bicuculline methiodide. The HFO was almost independent of the state of the system as estimated from the EEG pattern. Based on these findings we discuss whether bursts of action potentials triggered by the low-threshold calcium spike (LTS) can contribute to this pattern of visual thalamic activity.

EEG-dependent modulation of response dynamics of cat dLGN relay cells and the contribution of corticogeniculate feedback.

Single unit recordings were made extracellularly from the dorsal lateral geniculate nucleus (dLGN) in the anaesthetized and paralysed cat. The impulse rates of phasic (peak) and tonic components of visual responses to stimulation of the receptive field center by a flashing spot were determined during different states of the EEG, during local cortical cooling and during micro-iontophoretic application of the excitatory amino acid receptor agonists, quisqualate (QUIS) and N-methyl-D-aspartate (NMDA). Typically, visual responses were phasic during low frequency/high amplitude EEG patterns, resembling slow wave sleep (SWS). During high frequency EEG patterns (non-SWS) visual responses of X- and Y-cells exhibited a prominent tonic response component. This tonic component could be clearly reduced during ipsilateral cortical cooling in the non-SWS state. QUIS or NMDA, applied in order to mimic corticofugal activity, augmented the tonic response component, most efficiently during SWS EEG. The effects did not differ significantly for X- and Y-cells. During non-SWS EEG Y-cells exhibited a tonic response component similar to X-cells, but because of their higher peak rates the responses of Y-cells were on average more phasic than those of X-cells. Our results indicate that state-dependent changes in CNS activity modulate dL'GN responsiveness in part via the corticogeniculate feedback, and that predominantly the tonic response component is modulated.

Retinogeniculate transmission by NMDA and non-NMDA receptors in the cat.

The contributions of N-methyl-D-aspartate (NMDA) and non-NMDA excitatory amino acid (EAA) receptors to retinogeniculate transmission were investigated in the cat. The EAA antagonists 2-amino-5-phosphonovaleric acid (APV) and kynurenic acid (KYN) were used to block the NMDA receptors and all EAA receptors, respectively. Antagonistic effects on the visual response were assessed with single On/Off stimuli of 2 s duration or repetitive flicker stimulation (5 Hz) with a light spot projected onto the receptive field center. With APV, the NMDA response could be almost completely abolished but the visual response to repetitive stimulation was reduced on average by only 34%. Initial (transient) components of the single flash response were attenuated on average by 23%, the residual (sustained) component by 48%. With KYN the responses to NMDA, quisqualate (QUIS) and glutamate (GLU) were abolished or strongly reduced as was the visual response to flicker (mean 58%) and single flash stimulation (mean transient 73%, sustained 90%). Prolonged iontophoretic applications of the agonists GLU, QUIS and NMDA revealed receptor desensitization or competitive interactions with the naturally released transmitter in a dose-dependent manner. When the responses to any of the 3 agonists declined during continuous application, superimposed visual responses were clearly reduced in amplitude. Visual response amplitudes were also reduced when superimposed on steady state QUIS responses but unchanged in amplitude when superimposed on steady state NMDA responses. In conclusion, non-NMDA as well as NMDA receptors seem to participate in cat retinogeniculate transmission. Non-NMDA receptors appear to be most important for the initial component but can also maintain the visual response, while the NMDA receptors seem to be more effective during the later component of the response.

Linear and non-linear components in the centre-surround response of X- and Y-cells in the cat lateral geniculate nucleus.

Thalamocortical projection cells of cat dorsal lateral geniculate nucleus (dLGN) have been described to exhibit different types of non-linear integration of spatial contrast in addition to the linear integration inside their classical receptive field (CRF). We analysed whether a single mechanism might generate the two harmonic distortions of a linear response elicited inside the CRF and the shift effect elicited from regions outside the CRF. Therefore, both non-linear response types were investigated with identical stimulus conditions in the same cell. A quantitative analysis revealed that both response types can be elicited in nearly all Y-cells and in at least 50% of the X-cells. With blockade of GABA(A) inhibition by bicuculline methiodide (BICU) the number of X-cells with shift effect (SE) and second harmonics (2H) increased to more than 80%. Both, SE and 2H exhibited significantly correlated variations in their response-amplitude and -latency and in the frequency of their occurrence with changes in stimulus parameters (contrast, spatial frequency, area) and during BICU application. We assume that both non-linear contrast responses, the SE and the 2H might depend on the same (most probably retinal) mechanisms. We further suggest that the principal organisation of X- and Y-cell receptive fields might be very similar and that the differing spatial contrast responses may result from the different spatial resolution of their CRF subunits.

Spinal projections to the dorsal column nuclei in pigeons.

The dorsal column (DC) system was investigated in the pigeon by electrophysiological and anatomical methods. Field potentials recorded from the dorsal column nuclei (DCN) and evoked by electrical stimulation of cutaneous nerves showed two peaks in the case of wing nerve stimulation and one peak with leg nerve stimulation. Lesions of the DC or the ipsilateral dorsolateral funiculus (DLF) at a high cervical level (C4) indicate that a main input exists from the wing through the DC and from the leg through the DLF. With small injections of the fluorescent dye Fast blue into parts of the DCN it could be shown that aside from a primary afferent projection a well-developed postsynaptic dorsal column system exists only for the wing and that it takes its origin in the neurons of the lamina IV of the spinal dorsal horn.

Cells of origin of ascending pathways in the spinal cord of the pigeon.

Horseradish peroxidase was applied to ascending spinal pathways at high cervical levels to determine the cells of origin of these pathways in the pigeon. In addition to primary afferent fibers many ipsilaterally located lamina IV neurons of cervical segments project to the dorsal columns, indicating a substantial postsynaptic dorsal column pathway in birds. Cells projecting in the dorsolateral part of the white matter were predominantly located in lamina I and V throughout the spinal cord (bilaterally) and in the avian Clarke's column (ipsilateral at cervical and contralateral at lumbar levels). Neurons in the ventral horn (laminae VI-VIII) project to lateral and ventral parts of the lateral funiculus.

The Barmer study: impact of standardized warming of the injection site to enhance insulin absorption and reduce prandial insulin requirements and hypoglycemia in obese patients with diabetes mellitus.

BACKGROUND: The primary objective of this prospective controlled study was to investigate the impact of standardized injection-site warming on prandial rapid acting insulin dose and glycemic control when studied under real-world conditions. METHODS: All 145 participating patients (51 female, 94 male, 13 type 1 and 132 type 2 patients, age: 61.6 ± 8.4 yrs, HbA1c: 7.19 ± 0.50%) were treated with intensive insulin glargine and short-acting insulin analog therapy. After a 4 week treatment optimization run-in period, patients were randomized to continue therapy for three months without (control) or with a local injection-site warming device (InsuPad * ). Observation parameters included HbA1c, insulin dose, frequency of hypoglycemia, body weight and adverse events. RESULTS: HbA1c improved in both arms until study end (control group: 6.3 ± 0.5%; injection-site warming device: 6.3 ± 0.5%; both p < 0.001 vs. baseline). To achieve this good control, patients in the control group needed to increase the daily prandial insulin dose by 8.1% (from 66 ± 31 U to 71 ± 38 U, p < 0.05) with stable basal insulin requirements. Patients who used the injection-site warming device required less prandial insulin (70 ± 43 U to 55 ± 34 U; -19%, p < 0.001) and slightly more basal insulin (+3.9%). Total daily insulin dose increased in the control group (+3.7%) and decreased with warming device use (-8.6%, p < 0.001). The number of hypoglycemic events (<63 mg/dL) during the observation period was higher in the control group (6.2 ± 9.9/patient vs. injection-site warming device: 3.3 ± 4.8/patient, p < 0.05). Main study limitations can be seen in the open label design reliability of the collected dose information and the very obese patient cohort. CONCLUSION: When treating obese patients to target with insulin therapy, use of an injection-site warming device for 3 months resulted in a lower frequency of hypoglycemic events and a reduction in prandial insulin analog requirements. If these results are confirmed in other patient populations, an injection-site warming device may be useful in achieving treatment targets with a safer and more efficient basal bolus therapy in insulin-treated patients with type 1 and type 2 diabetes.